26 April 2019 EMA/CHMP/170631/2019 Committee for Medicinal Products for Human Use (CHMP) Assessment report Xromi International non-proprietary name: hydroxycarbamide Procedure No. EMEA/H/C/004837/0000 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. Official address Domenico Scarlattilaan 6 ● 1083 HS Amsterdam ● The Netherlands Address for visits and deliveries Refer to www.ema.europa.eu/how-to-find-us Send us a question Go to www.ema.europa.eu/contact Telephone +31 (0)88 781 6000 An agency of the European Union © European Medicines Agency, 2019. Reproduction is authorised provided the source is acknowledged. Administrative information Name of the medicinal product: XROMI Applicant: Nova Laboratories Ireland Limited 3rd Floor, Ulysses House Foley Street Dublin 1 D01 W2T2 IRELAND Active substance: HYDROXYCARBAMIDE International Nonproprietary hydroxycarbamide Name/Common Name: Pharmaco-therapeutic group Other antineoplastic agents (ATC Code): (L01XX05) Therapeutic indication(s): Prevention of vaso-occlusive complications of Sickle Cell disease in patients over 2 years of age. Pharmaceutical form(s): Oral solution Strength(s): 100 mg/ml Route(s) of administration: Oral use Packaging: bottle (HDPE) Package size(s): 1 bottle Assessment report EMA/CHMP/170631/2019 Page 2/133 Table of contents 1. Background information on the procedure ............................................ 10 1.1. Submission of the dossier .................................................................................... 10 1.2. Steps taken for the assessment of the product ....................................................... 11 2. Scientific discussion .............................................................................. 13 2.1. Introduction....................................................................................................... 13 2.2. Quality aspects .................................................................................................. 14 2.2.1. Introduction .................................................................................................... 14 2.2.2. Active substance ............................................................................................. 14 2.2.3. Finished medicinal product ................................................................................ 15 2.2.4. Discussion on chemical, and pharmaceutical aspects ............................................ 18 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ...................... 19 2.2.6. Recommendation for future quality development ................................................. 19 2.3. Non-clinical aspects ............................................................................................ 19 2.3.1. Introduction .................................................................................................... 19 2.3.2. Pharmacology ................................................................................................. 19 2.3.3. Pharmacokinetics............................................................................................. 20 2.3.4. Toxicology ...................................................................................................... 21 2.3.5. Ecotoxicity/environmental risk assessment ......................................................... 24 2.3.6. Discussion on non-clinical aspects...................................................................... 25 2.3.7. Conclusion on the non-clinical aspects ................................................................ 28 2.4. Clinical aspects .................................................................................................. 29 2.4.1. Introduction .................................................................................................... 29 2.4.2. Pharmacokinetics............................................................................................. 30 2.4.3. Pharmacodynamics .......................................................................................... 49 2.4.4. Clinical efficacy ............................................................................................... 53 2.4.5. Discussion on clinical efficacy ............................................................................ 89 2.4.6. Conclusions on clinical efficacy .......................................................................... 92 2.4.7. Clinical safety .................................................................................................. 92 2.4.8. Post marketing experience .............................................................................. 112 2.4.9. Discussion on clinical safety aspects................................................................. 115 2.4.10. Conclusions on clinical safety aspects ............................................................. 117 2.5. Risk Management Plan ...................................................................................... 117 2.6. Pharmacovigilance ............................................................................................ 125 2.7. Product information .......................................................................................... 126 2.7.1. User consultation ........................................................................................... 126 3. Benefit-risk balance ............................................................................ 126 3.1. Therapeutic Context ......................................................................................... 126 3.1.1. Disease or condition ....................................................................................... 126 3.1.2. Available therapies and unmet medical need ..................................................... 126 3.1.3. Main clinical studies ....................................................................................... 127 3.2. Favourable effects ............................................................................................ 128 3.3. Uncertainties and limitations about favourable effects ........................................... 128 3.4. Unfavourable effects ......................................................................................... 129 3.5. Uncertainties and limitations about unfavourable effects ....................................... 129 Assessment report EMA/CHMP/170631/2019 Page 3/133 3.6. Benefit-risk assessment and discussion ............................................................... 129 3.6.1. Importance of favourable and unfavourable effects ............................................ 129 3.6.2. Balance of benefits and risks ........................................................................... 130 3.6.3. Additional considerations on the benefit-risk balance ......................................... 130 4. Recommendation ................................................................................. 130 Assessment report EMA/CHMP/170631/2019 Page 4/133 List of abbreviations ACS Acute Chest Syndrome AE Adverse event AF Application Form ALT Alanine Transaminase AML Acute Myeloid Leukaemia ANC Absolute Neutrophil Count ANOVA Analysis of Variance AR Assessment Report ARC Absolute Reticulocyte Count AS Active Substance AUC Area Under (Plasma Concentration-Time) Curve AUC0-inf Plasma Concentration Time Curve Extrapolated to Infinity AUC0-t Plasma Concentration Time Curve Calculated to the Last Measured Concentration AUC%extrap Percentage of the Area Under the Curve extrapolated to infinity BABY HUG A phase III double-blinded, multi-centre, randomised, placebo-controlled infant hydroxycarbamide study BCS Biopharmaceutical Classification System BP British Pharmacopoeia b.w. Body weight CAPA Corrective and Preventive Actions CAS Chemical Abstracts Service CEP Certificate of Suitability to the monographs of the European Pharmacopoeia cfu Colony-forming unit CHMP Committee for Medicinal Products for Human Use CI Confidence Interval CL/F Clearance Cmax Concentration Maximum CMDh Coordination Group for Mutual Recognition and Decentralised Procedures – Human COMP Committee for Orphan Medicinal Products CRS Chemical Reference Standard CTD Common Technical Document Assessment report EMA/CHMP/170631/2019 Page 5/133 CV Co-efficient of Variation DAD Diode-Array Detector DMT Disease modifying therapy DNA Deoxyribonucleic acid EC European Commission ECG Electrocardiogram EDQM European Directorate for the Quality of Medicines EDTA Ethylenediaminetetraacetic acid EEA European Economic Area EMA European Medicines Agency EPO Erythropoietin ESRD End Stage Renal Disease EU European Union EUDRA-GMDP EU database on manufacturing, import and wholesale-distribution authorisations, and good manufacturing-practice (GMP) and good-distribution-practice (GDP) certificates FDA Food and Drug Administration FP Finished Product FT-IR Fourrier Transform Infrared Spectroscopy g Gram GCP Good Clinical Practice GD Gestation Day GLP Good Laboratory Practice GMP Good Manufacturing Practice GVP MV Good Vigilance Practice Module V Hb Haemoglobin HbF Foetal Haemoglobin HbS Sickle Haemoglobin HC Hydroxycarbamide HDPE High-density polyethylene HIV Human Immunodeficiency Virus HPLC High-Performance Liquid Chromatography HSCT Haematopoietic Stem Cell Transplantation HU Hydroxyurea HUSOFT Hydroxyurea Safety and Organ Toxicity study Assessment report EMA/CHMP/170631/2019 Page 6/133 HUSTLE Hydroxyurea Study of Long-Term